The present invention is an important advancement in the fields of endogenous pharmacotherapeutics, electromagnetic medicine, wound physiology and treatment, and regulation of the cell cycle, and has specific application in the area of wound healing, and in particular, the healing of chronic wounds, such as pressure ulcers, diabetic ulcers and venous stasis ulcers. Prior to discussing the present invention in detail, it is helpful to understand the specific mechanisms of wound healing, the immediate need for wound healing therapies, and the current state of the art.
While the specific mechanisms of action have not been fully determined, research over the past several years has substantially increased understanding of the nature of wound healing and the elegant cascade of signaling events necessary for the initiation of cell growth and migration and tissue regeneration, which collectively constitute the wound healing process. Importantly, numerous biochemical mediators of cell migration patterns and cell-cell/cell-extracellular matrix interactions involved in the reformation of tissue/organ systems have been identified.
There are distinct phases associated with the process of wound healing. In the inflammatory phase, platelets aggregate to deposit granules, which promote fibrin deposition, and stimulate the release of growth factors. Leukocytes migrate to the wound site and begin to digest and transport debris away from the wound. It is also during the inflammatory phase that monocytes are converted to macrophages, which release growth factors for stimulating angiogenesis and the production of fibroblasts. Next, in the proliferative phase, granulation tissue forms and epithelialization begins. Fibroblasts, key cell types in this phase, proliferate and synthesize collagen to fill the wound and provide a strong matrix on which epithelial cells grow. As collagen is produced by fibroblasts, vascularization extends from nearby vessels to supply nutrients to the regenerating tissue. The red loops of blood vessels give the wound a granular appearance, thus the term granulating. Epithelialization involves the migration of epithelial cells from the wound surfaces to seal the wound. Epithelial cells are driven by the need to contact cells of like type and are guided by a network of fibrin strands which function as a grid over which these cells migrate. Contractile cells called myofibroblasts appear in wounds and aid in wound closure. These cells exhibit collagen synthesis and contractility, and are common in granulating wounds. In the final phase of wound healing, the differentiation or tissue remodeling phase, collagen in the scar undergoes repeated degradation and resynthesis. It is during this phase that the tensile strength of the newly formed skin increases.
Clearly, growth factors are important messengers in coordinating this complex orchestration of cellular events. Today, growth factors refer to an expanding class of molecules, sometimes with specificity for certain types of cells, that can have either pro-proliferative or antiproliferative/differentiation effects, depending upon the specific circumstances. Their immediate molecular targets are specific members in the superfamily of receptor tyrosine kinases. Relatively little is known about the regulation of growth factor activity, but spatial and temporal gradients of growth factor and receptor expression are evident, and expression of a given growth factor or its receptors can be induced by other growth factors, suggesting that sequences of growth factor-mediated messages networked across cell types and integrated with other signaling cascades are central to tissue/organ development, maintenance and healing processes.
Thus, the recent realization that growth factors can serve as paracrine, autocrine, juxtacrine and intracrine (which refers to actions of growth factors within a cell) signals to regulate proliferation, migration, and interaction of cells critical to wound healing is important to understanding and developing wound treatments. For example, central to tissue/organ repair and remodeling is the critical revascularization of damaged tissue. Vascular endothelial growth factor (VEGF) is a recently discovered agent that promotes proliferation and migration of endothelial cells. Stimulating the expression of VEGF receptors in endothelial cell precursors allows those cells to respond to VEGF secreted from other cells or to VEGF acting via autocrine/intracrine mechanisms. Stimulating the release of VEGF from fibroblasts and/or other cell types (or stimulating VEGF production in endothelial cells) promotes mitotic and/or migratory activity of endothelial cells. Also critical to tissue repair is establishment of the extracellular scaffold to support cell migration and/or proliferation. Stimulating the release of agents such as fibroblast growth factors (FGF) from any of a number of cell types promotes proliferation and migration of fibroblasts, which are involved in production of extracellular matrix materials such as collagen. Moreover, stimulating FGF receptor production in fibroblasts capable of recognizing paracrine, autocrine, or intracrine FGF also plays a role in stimulating fibroblast activity and the production of extracellular matrix. Other agents implicated in tissue repair include insulin-like, platelet, transforming, and epidermal growth factors. Those molecules and their receptors are the likely molecular substrates for tissue repair. Endothelial cells, fibroblasts and keratinocytes, among others, are the cell types whose activity is critical to tissue repair and represent the likely cellular targets for these growth factors and related molecules associated with the healing of pressure sores.
It is also well known that regulatory signals normally found in the repair of acute wounds are not present in chronic wounds such as pressure ulcers and venous stasis ulcers. For example, chronic wounds frequently have poorly vascularized, thick fibrotic scar tissue surrounding the wound bed, are characterized by keratinocytes incapable of proliferation and migration, and have few active fibroblasts. These occurrences are clearly indicative of defects in growth factor signaling.
With the understanding that defects in growth factor signaling contribute to the development and/or persistence of chronic wounds, it is logical to conclude that reinstitution or normalization of that signaling would promote wound healing. Growth factors have been considered candidate therapeutics for wound healing because they are synthesized by and stimulate cells required for tissue repair, they are deficient in chronic wounds, and there is some evidence that pharmacological application enhances wound repair in a variety of animal models of dermal incisional and excisional repair.
However, clinical studies have been disappointing and some experts have suggested that an alternative to single growth factors as therapeutic agents is the utilization of growth factors in combination to elicit synergistic clinical efficacy. This lack of therapeutic efficacy may be in part because wound healing is a complex programmed sequence of cellular and molecular events, including macrophage activation during inflammation, cell migration, angiogenesis, provisional matrix synthesis, synthesis of collagen by fibroblasts, and reepithelialization. Current pharmaceutical approaches do not fully mimic the necessary spatial and temporal patterns of growth factor activity needed to promote wound healing. Overall, the complexity and variability of clinical wounds have limited pharmacological approaches to accelerate wound healing, leaving dressings and nonpharmacological ancillary modalities to dominate the market associated with wound management.
A treatment regimen involving application of outside or exogenous growth factors and other medicinal agents to the wound site is but one approach that has been pursued in the treatment of wound healing. Various medical treatment devices utilizing physical energy emissions to stimulate wound healing have also been developed over the past 40-50 years. Most of these devices involve the use of applied electrical currents to stimulate growth in bone or soft tissue. Another major group of devices utilizes the passage of electrical currents through coils of wire to create magnetic fields which are applied either by placing the coil in proximity to the human body or by wrapping the coils around the body or limb. Finally, a number of devices have been developed which utilize an antenna or tank circuit to apply Radio Frequency (RF) electromagnetic energy to the body for the purposes of medical treatment. Most devices in this latter category utilize continuous energy output to create thermal energy within the tissue. However, a subcategory of these devices utilize pulsed electromagnetic energy output to theoretically stimulate tissue without inducing a thermal response, although this has never been completely proven to occur using existing devices. There have been observations that some of these devices appear to stimulate or accelerate the wound healing process but there has been no sound, scientific data offered to explain how such devices might work at the cellular or molecular levels.
One area in which health care professionals and insurance providers are demanding improved treatment regimes is in the treatment of chronic wounds. In the United States, where wound care constitutes less than 1% of aggregate health care dollars, treating and managing pressure ulcers requires an inordinate amount of material, human resources, time and money. The costs associated with managing just one type of chronic wound alone, pressure ulcers, are extraordinary.
To enhance quality and decrease the cost of health care, the Agency for Health Care Policy and Research (AHCPR) was established by the U.S. government in 1989. That agency published Clinical Practice Guidelines for both prevention and treatment of pressure ulcers in 1992 and 1994, respectively. The release of these guidelines substantially increased biomedical awareness of patients with pressure ulcers, including the elderly and those afflicted with various spinal and neurological disorders. Importantly, the Health Care Financing Administration (HCFA) utilizes these guidelines to create medical policy and reimbursement criteria. Electrotherapeutic modalities are the only type of adjunctive therapy recommended in the AHCPR Clinical Practice Guideline and supported by the Nation Pressure Ulcer Advisory Panel.
Electrotherapy includes various means for applying an electric or electromagnetic field to a wound area to facilitate growth and proliferation of new tissue, i.e., healing. Application of external electrical and electromagnetic fields is now an increasingly standard therapy for the treatment of nonunion bone fractures, but these devices have seen limited use in other areas of healing.
Clinical research has shown that treatment with electrical stimulation or electromagnetic fields can enhance the healing rate of pressure ulcers unresponsive to conventional therapy. For example, pulsed electrical stimulation has been shown to enhance the healing rate of decubitus ulcers. This therapeutic approach stems from observations for nearly 60 years that electric potentials over wounds are negative until healed, and the related hypothesis that living tissues possess direct current surface potentials that regulate the proliferative phase of healing and that healing can be induced by negative electrical potential. Unfortunately, this has led to unsubstantiated claims that electrical stimulation cures a wide variety of health problems, thereby alienating the medical profession. Though this idea is now archaic and simplistic in view of scientific studies of the cellular correlates of wound healing, the evidence suggests that electrical fields accelerate wound healing. While few well designed experiments concerning cellular mechanisms have been conducted, some published reports indicate that electrical stimulation activates macrophages and increases cell proliferation, collagen synthesis and the expression of fibroblast receptors for transforming growth factor-beta.
Treatment devices emitting magnetic and/or electromagnetic energy offer significant advantages over other types of electrical stimulators because magnetic and electromagnetic energy can be applied externally through clothing and wound dressings, thereby rendering such treatments completely non-invasive. Moreover, published reports of double blind placebo-controlled clinical trials utilizing a RF transmission device (Diapulse) suggest that this ancillary treatment device significantly reduces wound healing time for chronic pressure ulcers as well as for surgical wounds. Studies using Dermagen, a magnetic device manufactured in Europe which produces a low frequency magnetic field, have demonstrated significant augmentation of healing of venous stasis ulcers. Additionally, it has been shown that 50% fewer patients treated with electromagnetic energy develop reoccurring pressure ulcers, compared to control patients, suggesting that electromagnetic energy treatments impart some resistance to the reoccurrence of chronic wounds, such as pressure ulcers. Electromagnetic energy may also be useful as a preventative strategy. Perhaps most important from a practical clinical perspective, an actuarial analysis of the effects of electromagnetic energy on the treatment of pressure ulcers show that this treatment, by reducing healing time by an average of 50%, results in significant reductions in the costs associated with wound management.
One category of prior art magnetic/electromagnetic treatment devices utilizes the passage of electrical currents through coils of wire to create magnetic fields. The frequency of the electrical impulses is relatively low, typically in the low frequency or audio range. Other devices, which utilize electrical stimulation between electrodes, represent a substantially different approach to medical treatment from the present invention for the primary reason that such an approach is invasive and more difficult to use and involves the attachment of electrodes at or near the wound site.
Another category of prior art electromagnetic treatment apparatus includes high frequency, high power devices utilizing pulsed electromagnetic energy output to stimulate tissue without inducing a thermal response. This category of devices is represented by the inventions disclosed in the following U.S. patents: Milinowski, U.S. Pat. Nos. 3,043,310 and 3,181,535; Kendall U.S. Pat. No. 3,543,762; Pearo U.S. Pat. No. 3,670,737; and most recently Rauch et. al., U.S. Pat. No. 5,584,863. Those earlier inventions first described and defined the principle and operation of pulsed, high frequency energy output devices and/or systems.
While numerous high frequency devices using pulsed electromagnetic energy to stimulate tissue growth have been developed, none have effectively addressed the needs of patients and health care providers. A recent attempt, as described in U.S. Pat. No. 5,584,863, is a pulsed radio frequency electrotherapeutic system having a pulse generator and an athermapeutic applicator head. The generator includes a power supply electrically connected to a remote current source by a cord, an exciter for generating pulsed signals of a selectable megahertz frequency, and an amplifier for amplifying the pulsed signals. A system controller having manually operable dials is provided for controlling pulse width duration, pulse burst repetition rate and power amplitude of the pulsed signals generated by the exciter. The amplitude of the signals outputted from the amplifier are compared with a reference value using a standing wave ratio (SWR) detector circuit, which in turn outputs power and impedance compensated signals to the applicator and produces a ratio signal that is delivered to the controller for adjusting the amplitude and phase of the signals generated by the exciter. The applicator, which includes a pair of spaced capacitor plates, a magnetic coil wound in a plane parallel to and electrically connected to the plates, and an RF shield, induces the received compensated signals into the tissue to be treated. Reactance and power level of the output of the applicator are manually controlled using an external tuning means connected to one of the capacitors. The device disclosed in U.S. Pat. No. 5,584,863 has high power requirements, requires numerous manual adjustments for effective operation, incorporates only a single applicator, fails to ensure constant, known and replicable treatment dosage outputs, and provides no confirmation that the applicator is properly located during treatment.
While the various and several prior art inventions, as described in the above referenced patents, produce electrical, magnetic or electromagnetic fields for treatment of tissue, virtually none of the prior art describes any credible cellular or physiological or molecular processes by which such energy fields specifically alter, induce or otherwise make happen an increase in cell growth, proliferation or density.
Additionally, none of the previous high frequency, high power devices utilizing pulsed electromagnetic energy output adequately addresses such practical design concerns as ease of use, simultaneous treatment of multiple wound sites on the same patient, dosage measurement, monitored dosage control and/or dosage compliance.
It would be desirable therefore to provide a method of and an apparatus for treating wounds with high frequency pulsed electromagnetic energy that is easy to implement, requiring minimal training in its proper and effective use, assures a constant, known and replicable dosage output, provides for simultaneous treatment of multiple wound sites, has low power requirements and is cost effective.
Citation of the above documents, devices and studies is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein.